Dept. Biology, Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline Medicines Research Centre, Verona, Italy.
Schizophr Res. 2011 May;128(1-3):7-14. doi: 10.1016/j.schres.2011.01.021. Epub 2011 Feb 24.
Evidence has accumulated over the past years that dysregulation of glutamatergic neurotransmission maybe implicated in the pathophysiology of schizophrenia. Glutamate acts on two major classes of receptors: ionotropic receptors, which are ligand-gated ion channels, and metabotropic receptors (mGluRs), coupled to heterotrimeric G-proteins. Although several pharmacological evidences point to abnormal glutamatergic transmission in schizophrenia, changes in the expression of glutamatergic receptors in the prefrontal cortex of patients with schizophrenia remains equivocal. In the present work, we have investigated glutamatergic neurotransmission in schizophrenia by assessing the expression in Brodmann Area 10 of mGluR5, the AMPA receptor subunits GluR1 and GluR2, and Na(+)/K(+) ATPase-α1, a potential modulator of glutamate uptake in the brain. Semiquantitative analysis of the expression of these proteins from postmortem brains revealed a particularly prominent reduction of GluR1 and GluR2 expression in patients with schizophrenia vs the control group. Conversely, we observed an up-regulation in the levels of Na(+)/K(+) ATPase-α1 expression. Finally, no change in the protein levels of mGluR5 was observed in schizophrenia. Our findings support and expand the hypothesis of glutamatergic dysfunction in prefrontal cortex in the pathophysiology of schizophrenia.
多年来的证据表明，谷氨酸能神经传递的失调可能与精神分裂症的病理生理学有关。谷氨酸作用于两类主要的受体：离子型受体，即配体门控离子通道，和代谢型受体（mGluRs），与异三聚体 G 蛋白偶联。尽管有几项药理学证据表明精神分裂症存在异常的谷氨酸能传递，但精神分裂症患者前额叶皮层中谷氨酸能受体的表达变化仍存在争议。在本工作中，我们通过评估 10 号布罗德曼区 mGluR5、AMPA 受体亚基 GluR1 和 GluR2 以及 Na(+)/K(+) ATPase-α1 的表达，研究了精神分裂症中的谷氨酸能神经传递，Na(+)/K(+) ATPase-α1 是大脑中谷氨酸摄取的潜在调节剂。这些蛋白质在死后大脑中的表达的半定量分析显示，与对照组相比，精神分裂症患者的 GluR1 和 GluR2 表达明显降低。相反，我们观察到 Na(+)/K(+) ATPase-α1 表达水平上调。最后，精神分裂症中 mGluR5 的蛋白水平没有变化。我们的研究结果支持并扩展了谷氨酸能功能障碍在前额叶皮层的病理生理学中的假说。
